Fight Aging!

This paper is an example of work exploring how exactly mitochondrial dysfunction might contribute to age-related atrial fibrillation, the dysregulation of heart rhythm. It is possibly more helpful as an introduction to the roots of atrial fibrillation, meaning dysfunction in electrical connectivity and remodeling of structure in heart tissue, and how those two issues relate to one another. A perhaps surprisingly large fraction of atrial fibrillation can be at least temporarily corrected via minimally invasive surgical techniques, because in those cases the issue arises from inappropriate electrical signaling originating in small areas of the heart and connecting vessels, but once age-related changes in the heart become more widespread and severe, this stops being the case.

Atrial fibrillation (AF) is a common arrhythmia in clinical practice that often leads to severe complications such as heart failure, myocardial infarction, and stroke. It is associated with increased mortality and a significantly reduced quality of life. Current treatments for AF include risk factor control, medications for rate and rhythm control, and anticoagulation. For refractory cases, interventional procedures like cardiac radiofrequency ablation are used. However, these treatments have limitations, including adverse effects such as bleeding and a significant risk of AF recurrence. Further elucidating the mechanisms of AF development and identifying precise intervention targets are urgently needed.

The pathogenesis of AF has not been fully elucidated, but the core pathological basis for its development and maintenance primarily involves two major mechanisms: atrial electrical remodeling and structural remodeling. Electrical remodeling is mainly manifested as abnormal ion channel function in atrial myocytes, resulting in a shortening of action potential duration and increased dispersion of the effective refractory period. This creates a substrate for reentrant arrhythmias. Structural remodeling, on the other hand, involves morphological changes such as atrial fibrosis, myocardial hypertrophy, and dilation, which further promote the persistence and stabilization of AF.

Recent studies have confirmed that mitochondrial dysfunction is a central hub driving these remodeling processes. As the energy factories of the cell, mitochondria generate adenosine triphosphate (ATP) through oxidative phosphorylation, providing the necessary energy for sustained contraction, ion pump operation, and electrical signaling in cardiomyocytes. In the AF state, atrial myocytes are subjected to rapid, disorganized, high-frequency electrical excitation. The dramatic increase in energy demand leads to mitochondrial overload and accelerates mitochondrial senescence and damage.

Mitochondrial dysfunction affects intracellular ionic homeostasis and membrane excitability through dual disruptions of energy crisis (ATP insufficiency) and oxidative stress (reactive oxygen species burst). These disruptions directly impair cardiomyocyte ion channel function and expression, driving the onset and progression of AF. Mitophagy, a key mechanism for mitochondrial quality control, selectively removes damaged mitochondria to prevent reactive oxygen species accumulation and preserve the healthy mitochondrial network. However, chronic AF-related stress (e.g., calcium overload, sustained reactive oxygen species exposure) can impair mitophagy pathways, resulting in the accumulation of dysfunctional mitochondria.

This study combined bioinformatics analysis and experimental validation to uncover key genes and molecular networks underlying the interaction between mitophagy and ion channels in AF. The objective was to elucidate the molecular mechanisms underlying the "mitophagy defects -> ion channel dysfunction -> electrical remodeling" axis.

Link: https://doi.org/10.3389/fphys.2025.1687578

Researchers here mine human data and records from zoos to show that male castration and female sterilization increase life span in a very broad range of higher animals. Mechanisms are thought to be similar from species to species, even if the size of the effect on life span varies. In males, it appears largely connected with systemic effects of exposure to androgen hormones over a lifespan, while in females it appears largely connected to stresses resulting from reproduction. Thus in males only hormone level reduction increases life span, while in females any contraceptive approach that prevents reproduction increases life span.

Our results demonstrate that ongoing hormonal contraception and permanent methods of surgical sterilization increase vertebrate survivorship. The analysis of zoo records provides unparalleled insight into the taxonomic breadth of the lifespan response, with male castration, female surgical sterilization and ongoing female hormonal contraception linked to increased life expectancy across a broad range of species within the mammalian kingdom.

Life expectancy is increased by an average of 10-20% depending on the timing of treatment and environment the animal is exposed to, providing strong evidence for the presence of an intraspecific trade-off between adult reproduction and survival in vertebrates. Notably, however, we do not observe the very substantial, often more than 50% increases in lifespan that are observed in some invertebrate species after germ cell removal, particularly in species that are semelparous.

There is a wide species-level heterogeneity in the survival response to sterilization and contraception. What causes this remains to be determined. It has been widely hypothesized that male gonadal-specific hormone production (testosterone) contributes to shorter lifespans in males relative to females. In rodents, castration is associated with improvements in several domains of health in later life, in particular cognition and physical function. Thus, reducing male androgen signalling may broadly target multiple processes involved in the biology of ageing.

In females, increased life expectancy occurred with various contraceptive methods. Contraception reduced the risk of death from multiple causes, including infectious and non-infectious diseases. We hypothesize that the increased life expectancy in females arises from reduced allocation to reproduction and reproductive processes in adulthood, with contraception strongly reducing the direct and indirect costs of offspring production.

Link: https://doi.org/10.1038/s41586-025-09836-9

The axons that carry nerve impulses between neurons must be sheathed in myelin if they are to function. This structured myelin is built and maintained by a specialized population of cells called oligodendrocytes, which derive from a precursor population. Loss of myelin is a feature of severely disabling and ultimately fatal conditions such as multiple sclerosis. To a lesser degree, however, myelin loss also takes place with advancing age, and evidence suggests that this contributes to cognitive decline at the very least. Anything that disrupts the activity of oligodendrocytes will lead to loss of myelin, and the underlying damage that drives aging disrupts all cell populations in a variety of ways, to an increasing degree as the burden of damage rises over time.

The connection with aging is why it is worth keeping an eye on progress towards the development of therapies for multiple sclerosis. Therapies that treat demyelinating conditions may turn out be useful in older people as well. The details do matter, however. The targeted mechanisms must be applicable in both disease and aging, and it isn't always clear that this is the case. Today's open access paper is an example in which the researchers focus on multiple sclerosis patients and animal models of demyelination that have no relevance to aging. Thus the target they uncover does seem promising, but may or may not turn out to be useful outside the scope of multiple sclerosis.

The CEMIP Hyaluronidase is Elevated in Oligodendrocyte Progenitor Cells and Inhibits Oligodendrocyte Maturation

Central nervous system (CNS) demyelination occurs in numerous conditions including multiple sclerosis (MS). CNS remyelination involves recruitment and maturation of oligodendrocyte progenitor cells (OPCs). Remyelination often fails in part due to the inhibition of OPC maturation into myelinating oligodendrocytes (OLs). Digestion products of the glycosaminoglycan hyaluronan (HA), generated by hyaluronidase activity, block OPC maturation and remyelination. Here, we aimed to identify which hyaluronidases are elevated in demyelinating lesions and to test if they influence OPC maturation and remyelination.

We find that the Cell Migration Inducing and hyaluronan binding Protein (CEMIP) is elevated in demyelinating lesions in mice with experimental autoimmune encephalomyelitis during peak disease when neuroinflammatory mediators, including tumor necrosis factor-α (TNFα), are at high levels. CEMIP expression is also elevated in demyelinated MS patient lesions. CEMIP is expressed by OPCs, and TNFα induces increased CEMIP expression by OPCs. Both increased CEMIP expression and HA fragments generated by CEMIP block OPC maturation into OLs. CEMIP-derived HA fragments also prevent remyelination in vivo.

This data indicates that CEMIP blocks remyelination by generating bioactive HA fragments that inhibit OPC maturation. CEMIP is therefore a potential target for therapies aimed at promoting remyelination.

Mitochondria retain a circular genome distinct from the DNA of the cell nucleus, a legacy of their distant evolutionary origins as symbiotic bacteria. Mitochondrial DNA damage is thought to contribute to the characteristic mitochondrial dysfunction of aging, although the relative contributions of mitochondrial DNA damage versus epigenetic changes in the nucleus that disrupt mitochondrial function remain up for debate. Researchers here provide evidence for a novel form of molecular damage to mitochondrial DNA to contribute to mitochondrial dysfunction. Once again, the question of relative contributions arises, always a challenge in everything associated with mechanisms of aging.

Mitochondrial DNA (mtDNA) is crucial for cellular energy production, metabolism, and signaling. Its dysfunction is implicated in various diseases, including mitochondrial disorders, neurodegeneration, and diabetes. mtDNA is susceptible to damage by endogenous and environmental factors; however, unlike nuclear DNA (nDNA), mtDNA lesions do not necessarily lead to an increased mutation load in mtDNA. Instead, mtDNA lesions have been implicated in innate immunity and inflammation.

Here, we report a type of mtDNA damage: glutathionylated DNA (GSH-DNA) adducts. These adducts are formed from abasic (AP) sites, key intermediates in base excision repair, or from alkylation DNA damage. Using mass spectrometry, we quantified the GSH-DNA lesion in both nDNA and mtDNA and found its significant accumulation in mtDNA of two different human cell lines, with levels one or two orders of magnitude higher than in nDNA.

The formation of GSH-DNA adducts is influenced by TFAM and polyamines, and their levels are regulated by repair enzymes AP endonuclease 1 (APE1) and tyrosyl-DNA phosphodiesterase 1 (TDP1). The accumulation of GSH-DNA adducts is associated with the downregulation of several ribosomal and complex I subunit proteins and the upregulation of proteins related to redox balance and mitochondrial dynamics. Molecular dynamics (MD) simulations revealed that the GSH-DNA lesion stabilizes the TFAM-DNA binding, suggesting shielding effects from mtDNA transactions.

Collectively, this study provides critical insights into the formation, regulation, and biological effects of GSH-DNA adducts in mtDNA. Our findings underscore the importance of understanding how these lesions may contribute to innate immunity and inflammation.

Link: https://doi.org/10.1073/pnas.2509312122

One can debate aspects of the way in which researchers here model what might happen if all of aging is controlled except random mutational damage to nuclear DNA, but the idea is an interesting one. Will random mutational damage to somatic cells be so much harder to eliminate than other aspects of aging that we should think ahead in this way? In tissues where cells are largely replaced, we might think that stem cell populations can at some point be repaired or replaced, and thus the mutational burden in tissues can be reduced over time via the influx of less damaged somatic cells created by the rejuvenated stem cell population. Most neurons in the central nervous system are long-lived, however, and are never replaced. We would have to postulate some very advanced technology to think that we will be able to address the stochastic mutational burden of vital cells in the brain, that damage different in every cell.

Somatic mutations accumulate with age and can cause cell death, but their quantitative contribution to limiting human lifespan remains unclear. We developed an incremental modeling framework that progressively incorporates factors contributing to aging into a model of population survival dynamics, which we used to estimate lifespan limits if all aging hallmarks were eliminated except somatic mutations.

Our analysis reveals fundamental asymmetry across organs: post-mitotic cells such as neurons and cardiomyocytes act as critical longevity bottlenecks, with somatic mutations reducing median lifespan from a theoretical non-aging baseline of 430 years to 169 years. In contrast, proliferating tissues like liver maintain functionality for thousands of years through cellular replacement, effectively neutralizing mutation-driven decline.

Multi-organ integration predicts median lifespans of 134-170 years - approximately twice current human longevity. This substantial yet incomplete reduction indicates that somatic mutations significantly drive aging but cannot alone account for observed mortality, implying comparable contributions from other hallmarks.

Link: https://doi.org/10.1101/2025.11.23.689982

Alzheimer's disease is the most prominent of the tauopathies. This is a class of neurodegenerative conditions in which large enough amounts of tau protein become excessively altered by phosphorylation and aggregate into solid deposits, causing inflammation, loss of function, and cell death in the brain. The various isoforms of tau play an important role in maintaining the structure of axons that connect neurons, but aggregation would be problematic regardless of the normal function of tau.

Just as much of Alzheimer's research and development has long focused on trying to prevent, clear, or disarm misfolded amyloid-β and its toxic aggregates, a similar range of efforts is focused on finding ways to prevent, clear, or disarm hyperphosphorylated tau and its aggregates. Progress to date has been frustrating slow, just as it was for amyloid-β clearance via immunotherapy. Many of the possible paths forward appear challenging to implement well.

Today's research materials present an example of the type, an approach that potentially allows dramatic reduction in overall tau levels. Yet tau is important to axonal function, one can't just get rid of it, which presents developers with the much harder goal of achieving a balancing act with dose and outcome. Even then it tends to be the case that therapies that treat a condition in which a protein becomes altered into a toxic form by reducing overall expression of that protein tend to have unpleasant side-effects.

Novel discovery reveals how brain protein OTULIN controls tau expression and could transform Alzheimer's treatment

The research team initially hypothesized that inhibiting the enzyme activity of the OTULIN protein would enhance tau clearance through cellular garbage disposal systems. However, when they completely knocked out the OTULIN gene in neurons, tau disappeared entirely - not because it was being degraded faster, but because it wasn't being made at all. "This was a paradigm shift in our thinking. We found that OTULIN deficiency causes tau messenger RNA to vanish, along with massive changes in how the cell processes RNA and controls gene expression."

The study used neurons derived from a patient with late-onset sporadic Alzheimer's disease, which showed elevated levels of both OTULIN protein and phosphorylated tau compared to healthy control neurons. This correlation suggested OTULIN might be contributing to disease progression. "OTULIN could serve as a novel drug target, but our findings suggest we need to modulate its activity carefully rather than eliminate it completely. Complete loss causes widespread changes in cellular RNA metabolism that could have unintended consequences."

The deubiquitinase OTULIN regulates tau expression and RNA metabolism in neurons

The degradation of aggregation-prone tau is regulated by the ubiquitin-proteasome system and autophagy, which are impaired in Alzheimer's disease (AD) and related dementias (ADRD), causing tau aggregation. Protein ubiquitination, with its linkage specificity determines the fate of proteins, which can be either protein degradative or stabilizing signals. While the linear M1-linked ubiquitination on protein aggregates serves as a signaling hub that recruits various ubiquitin-binding proteins for the coordinated actions of protein aggregate turnover and inflammatory nuclear factor-kappa B (NF-κB) activation, the deubiquitinase OTULIN counteracts the M1-linked ubiquitin signaling. However, the exact role of OTULIN in neurons and tau aggregates clearance in AD are unknown.

Based on our quantitative bulk RNA sequencing analysis of human induced pluripotent stem cell-derived neurons (iPSNs) from an individual with late-onset sporadic AD (sAD2.1), a downregulation of the ubiquitin ligase activating factors (MAGE-A2/MAGE-A2B/MAGE-H1) and OTULIN long noncoding RNA (OTULIN lncRNA) was observed compared to healthy control iPSNs. The downregulated OTULIN lncRNA is concurrently associated with increased levels of OTULIN protein and phosphorylated tau.

Inhibiting the deubiquitinase activity of OTULIN with a small molecule UC495 reduced the phosphorylated tau in iPSNs and SH-SY5Y cells, whereas the CRISPR-Cas9-mediated OTULIN gene knockout (KO) in sAD2.1 iPSNs decreased both the total and phosphorylated tau levels. CRISPR-Cas9-mediated OTULIN KO in SH-SY5Y resulted in a complete loss of tau at both mRNA and protein levels, and increased levels of polyubiquitinated proteins, which are being degraded by the proteasome. In addition, SH-SY5Y OTULIN KO cells showed downregulation of various genes associated with inflammation, autophagy, ubiquitin-proteasome system, and the linear ubiquitin assembly complex that consequently may prevent development of an autoinflammation in the absence of OTULIN gene in neurons.

Together, our results suggest, for the first time, a noncanonical role for OTULIN in regulating gene expression and RNA metabolism, which may have a significant pathogenic role in exacerbating tau aggregation in neurons. Thus, OTULIN could be a novel potential therapeutic target for AD and ADRD.

Like the gut microbiome, the composition of the oral microbiome changes with age. Some of these changes have been shown to correlate with health status, but research into this part of the commensal microbiome is nowhere near as advanced as is the case for the gut microbiome. It is unclear as to the degree to which the oral microbiome is causing issues in aging, even where mechanisms are known to exist, such as leakage of bacteria and bacterial products associated with gingivitis into the bloodstream. It is also unclear as to whether the classes of strategy shown to rejuvenate the composition of the gut microbiome can work effectively for the oral microbiome.

Evidence indicates that the composition of the oral microbiome changes with age, although findings on diversity are inconsistent, with reports of both increases and decreases in older adults. These shifts are influenced by factors such as diet, oral hygiene, and immune function. Unhealthy aging, including conditions like frailty, neurodegenerative diseases, and sarcopenia, is associated with distinct oral dysbiosis. Potential mechanisms linking the oral microbiome to aging include chronic inflammation and immunosenescence.

Although research on the oral microbiome is still in its early stage compared to that on the gut microbiome, existing studies still indicate a link between the oral microbiome and aging. The purpose of this review is to explore whether the oral microbiome, which serves as a common gateway for the microbiota of the respiratory and digestive systems, should be considered a target for predicting and delaying aging. We focus primarily on the changes in the oral microbiome during healthy aging, the characteristics of the oral microbiome in unhealthy aging states such as frailty and age-related diseases and the possible mechanisms underlying the association between the oral microbiome and aging. Finally, we summarize the current research findings and provide possible directions for microbiome-based aging interventions.

Link: https://doi.org/10.1080/20002297.2025.2589648

The balance of microbial populations making up the gut microbiome changes with age in ways that are detrimental to health. Microbes generating necessary metabolites diminish in number, while microbes that provoke chronic inflammation grow in number. Further, researchers have established that is a tendency towards a distinctly different gut microbiome composition in some age-related conditions, such as Alzheimer's disease. Whether this difference over and above the more usual age-related changes acts to contribute directly to Alzheimer's disease, or is a side-effect of a dysregulated immune system or other aspect of aged metabolism, remains to be concretely determined. Here, researchers focus on microglia, the innate immune cells of the brain. Dysfunctional, inflammatory microglia are thought to be involved in neurodegenerative conditions, and one can argue for a connection to the gut microbiome.

Alzheimer's disease (AD) is a complex neurodegenerative disorder that can be caused by multiple factors, such as abnormal amyloid-beta (Aβ) deposition, pathological changes in Tau protein, lipid metabolism disorders, and oxidative stress. For decades, research into AD has been dominated by the amyloid cascade hypothesis. However, amyloid-beta (Aβ) clearance alone slows progression by only 35%. This compels increasing attention to peripheral factors in AD pathophysiology, redirecting the field from a brain-centric, amyloid-focused model toward a systemic perspective that emphasizes peripheral-central interactions.

It is now increasingly recognized that chronic, low-grade systemic inflammation, a condition often termed "inflammaging," acts as a critical driver of neuroinflammation and accelerates neurodegenerative processes. Within this framework, the gastrointestinal tract, which harbors the body's largest immune cell population and the vast metabolic capacity of the gut microbiome, emerges as a pivotal hub for originating peripheral signals that shape brain health and disease. This article reviews the direct and indirect effects of gut microbiota and its derivatives on microglia, explores their role in the pathogenesis of AD, and discusses therapeutic strategies based on gut microbiota. Although existing studies have shown the potential of these interventions, further research is needed to completely understand their application in the treatment of AD.

Link: https://doi.org/10.3389/fragi.2025.1704047

Clearly change must occur constantly in the adult brain. However we suppose information to be encoded in physical structures of the brain, the information content of a brain evidently changes over time, as illustrated by the processes of memory and learning, and thus the structure of the brain must also change. Nonetheless, if one backtracks to the early 1990s, the consensus at the time was that new neurons were not created in the adult brain. Any change in the brain's information content was thought to be a matter of rearranging axonal connections between neurons or to involve alterations in other, smaller-scale structures such as dendritic spines. Then it was persuasively demonstrated that the creation of new neurons does in fact occur in adult mice.

In the grand scheme of progress in the life sciences, that something occurred thirty years ago makes it a relatively recent realization. Follow up and debate are still very much in progress. Over the past decade, a debate in the scientific literature occurred over whether the limited human data in fact supported the existence of adult neurogenesis in our own species. Matters appear to have settled to a consensus that human adult neurogenesis does occur. Nonetheless, it remains the case that most of the data for adult neurogenesis is (a) obtained from studies in mice, and (b) focused on the hippocampus, an important region for the function of memory.

Today's open access paper is a brief and readable review on the question of aging and neurogenesis in the hippocampus. Neurogenesis is interesting in this context because, as shown in mice, it declines with age. This is thought to contribute to loss of memory function, and there is a sizable contingent of researchers engaged in trying to boost neurogenesis as a possible basis for future therapies. As this review makes clear, however, after nearly thirty years of work on this topic there are still looming gaps in knowledge everywhere you look.

Extent and activity of adult hippocampal neurogenesis

There is strong evidence for human hippocampal neurogenesis occurring well into adulthood, albeit at a steadily decreasing rate, but we lack a cohesive scientific discourse surrounding its physiological role, particularly the relationship between neurogenic extent and activity. Research emphasis is generally on the former, relying on the assumption that the number of newborn neurons sufficiently explains any functional implications. This approach ignores the reality that individual neurons vary drastically in activity, even in otherwise identical cell populations. This review focuses on the relationship between the extent of neurogenesis and activity of the newborn neurons themselves, with a particular emphasis on how we might use this information to inform future studies.

Adult hippocampal neurogenesis is the process by which new neurons are generated in the dentate gyrus of the hippocampus in the adult brain. The generation of new neurons is a hierarchical, activity-dependent process that starts with radial glia-like precursors that quickly transition to progenitors before eventual differentiation into neuroblasts. This immature neuronal population matures and migrates a short distance from the subgranular zone of the dentate gyrus to the granular layer, where it integrates into pre-existing circuits.

Newly generated neurons progress through dynamic stages important for their normal functioning, finally resulting in behavioral modulation with their integration into hippocampal circuitry. This complex process is regulated by various factors that can increase or decrease neurogenesis, leading to alterations in both the number and function of newly generated neurons. For example, aging is a major physiological factor that contributes to the decline of adult hippocampal neurogenesis by pushing the neural stem cell pool into a quiescent stage and reducing the ability of neural stem cells to proliferate.

Even if the neural stem cells produce new neurons, aging impairs the survival and integration of these newborn neurons into existing circuits. Indeed, aging disrupts the dentate gyrus microenvironment by reducing synaptic density and compromising vascularization, ultimately creating a less supportive niche for neurogenesis. The dentate gyrus plays a critical role in pattern separation and episodic memory, and age-related reductions in hippocampal neurogenesis have been directly linked to cognitive decline; studies show that diminished neurogenesis contributes to impairments in spatial learning, memory precision, and cognitive flexibility, all hallmark features of age-related cognitive decline.

In nematode worms, SKN-1 is a known longevity-related gene, and researchers here explore its role in the lysosomal enlargement that occurs with aging. Lysosomes are necessary for the cellular maintenance processes of autophagy to function. Lysosomes carry out the last step in the recycling of damaged and excess proteins machinery and structures in the cell, which is to break down those materials into components that can be reused. It has been observed that lysosomes become larger in cells in aged tissues, but this is apparently a compensatory behavior rather than a form of dysfunction. It is an attempt to maintain lysosomal function and thus the health of the cell in the face of the damage of aging.

Lysosomes are critical hubs for both cellular degradation and signal transduction, yet their function declines with age. Aging is also associated with significant changes in lysosomal morphology, but the physiological significance of these alterations remains poorly understood. Here, we find that a subset of aged lysosomes undergo enlargement resulting from lysosomal dysfunction in C. elegans. Importantly, this enlargement is not merely a passive consequence of functional decline but represents an active adaptive response to preserve lysosomal degradation capacity. Blocking lysosomal enlargement exacerbates the impaired degradation of dysfunctional lysosomes.

Mechanistically, lysosomal enlargement is a transcriptionally regulated process governed by the longevity transcription factor SKN-1, which responds to lysosomal dysfunction by restricting fission and thereby induces lysosomal enlargement. Furthermore, in long-lived germline-deficient animals, SKN-1 activation induces lysosomal enlargement, thereby promoting lysosomal degradation and contributing to longevity. These findings unveil a morphological adaptation that safeguards lysosomal homeostasis, with potential relevance for lysosomal aging and life span.

Link: https://doi.org/10.1371/journal.pbio.3003540

Researchers here build an aging clock based on the expression levels of three microRNAs as a proof of principle that microRNA clocks are viable. This should not be a surprise; if the past twenty years of work on aging clocks have taught us anything, it is that any sufficiently complex body of data that changes with age can be used as the basis for a clock. Clocks are now relatively easily produced. The much harder challenge is to take any given clock and amass sufficient human data to (a) demonstrate that it is usefully measuring biological age or something closely related to biological age, and (b) understand its quirks and limitations to the point at which one can trust the use of that clock in the assessment of potential rejuvenation therapies, in order to guide and accelerate progress in the field.

The extension of human longevity has intensified the search for biomarkers that capture not only chronological age but also biological aging and functional healthspan. Among molecular candidates, microRNAs (miRNAs) have emerged as promising regulators and indicators of aging-related processes. In this pilot study, we explored whether selected circulating miRNAs could serve as potential biomarkers of biological age and lifestyle-associated aging dynamics.

Based on current literature, we focused on three miRNAs - miR-24, miR-21, and miR-155 - previously linked to inflammation, senescence, and metabolic regulation. Capillary blood samples from a heterogeneous adult cohort were analyzed using quantitative PCR. Values were integrated into a composite "miRNA-3Age" model through multivariate regression analysis to estimate biological age. Associations between lifestyle variables (diet, exercise, stress, and smoking) and miRNA-based biological age were examined.

The miRNA-3Age model predicted biological age with moderate correlation to chronological age and revealed variability consistent with individual health profiles. Participants with favorable lifestyle factors (e.g., frequent consumption of fish, whole grains, and green tea; regular exercise) tended to exhibit lower miRNA-3Age estimates, whereas stress and smoking were associated with higher predicted biological age. The miRNA-3Age model provides a preliminary step toward a scalable, lifestyle-sensitive aging metric that warrants validation in diverse populations.

Link: https://doi.org/10.3389/fnut.2025.1659730

Reprogramming involves exposing cells to expression of one or more of the Yamanaka factors, c-Myc, Oct4, Sox2, and KLF4. This slowly alters cell state in a small fraction of exposed somatic cells, and these cells transform to become induced pluripotent stem cells, essentially the same as embryonic stem cells. This recapitulates some of the processes involved in embryogenesis. More rapidly and reliably than this change of state, a cell exposed to Yamanaka factor expression also exhibits rejuvenation of nuclear DNA structure and patterns of gene expression, leading to a restoration of youthful function. This cannot fix everything in an aged cell, such as mutational DNA damage, but it has a sizable enough effect on cells, and in mice, that partial reprogramming as a basis for rejuvenation therapies has become a popular area of development.

Can reprogramming of cell state be efficiently separated from reprogramming of nuclear structure? If we want reliable rejuvenation therapies, it seems likely that progress must be made on this front. Researchers are investigating the regulation of reprogramming downstream of the Yamanaka factors, but this is a painfully slow process. Still, every incremental advance in tracing the interactions of proteins might be the one that disentangles rejuvenation from state change, unleashing a much more efficient approach than offered by the present options capable of triggering reprogramming.

Most of the longevity industry now consists of reprogramming initiatives if measuring by investment size. Related to that, we might argue that most of the work carried out on reprogramming as a basis for rejuvenation therapies is in fact conducted outside academia at this point. In the long run this work will become just as visible as academic efforts, but for now it is dark matter. Thus to find ongoing indications of progress on picking apart the systems of regulation that produce rejuvenation in response to Yamanaka factor expression, one must keep up with the publication of academic papers - such as today's example.

Conserved Master Regulators Orchestrate Cellular Reprogramming-Induced Rejuvenation

Partial somatic cell reprogramming has been proposed as a rejuvenation strategy, yet the regulatory architecture orchestrating age reversal remains unclear. What molecular systems allow partial relaxation of identity to restore youthful regulatory function while avoiding dedifferentiation? Previous work has identified chromatin regulators as central to this process. DNA methyltransferases Tet1 and Tet2 may be required for reprogramming-induced rejuvenation, and reprogramming-induced rejuvenated cells exhibit restored nucleosome regularity and recalibrated histone modification balance. However, identifying genes that change during rejuvenation does not reveal which factors actively drive the process versus those that respond as downstream consequences. Distinguishing upstream regulators from effector genes requires network-level analysis that can infer causal regulatory relationships.

Here, we performed gene regulatory network reconstruction across several independent systems to identify master regulators that coordinate reprogramming-induced rejuvenation (RIR). In mouse mesenchymal stem cells, mouse adipocytes, and human fibroblasts undergoing partial reprogramming, we identified genes showing opposite expression dynamics during aging and reprogramming. This approach revealed regulators governing rejuvenation rather than developmental programs. Despite divergent overall network architectures, nine transcription factors converged as master regulators across all three systems, including Ezh2, Parp1, and Brca1. These regulators undergo coordinated reorganization during reprogramming, characterized by broader target engagement and enhanced regulatory coherence.

We further demonstrated that direct perturbation of Ezh2 bidirectionally modulates transcriptomic age. Notably, overexpression of a catalytically inactive Ezh2 mutant achieved rejuvenation, suggesting mechanisms distinct from canonical H3K27me3-mediated regulation are involved in RIR. Our findings reveal that cellular rejuvenation is orchestrated by conserved master regulators whose network coordination can be targeted independently of the reprogramming process.

Senescent cells grow in number with age, lingering to cause harm via inflammatory secretions. This is a problem in every tissue. Here researchers focus on the endothelial lining of blood vessels, and demonstrate that a strategy to reduce the pace at which endothelial cells enter a senescent state can slow the development of vascular stiffness and atherosclerosis in a mouse model of these cardiovascular issues. There are many different ways in which one might go about making cells more resistant to stress-induced senescence, and here the approach is to improve cell defenses against oxidative molecules.

Terazosin (TZ), a well-known antagonist of the α1-adrenergic receptor (α1-AR), has demonstrated protective effects on vascular endothelial cells (ECs) and reduced vascular stiffness in clinical studies. Endothelial dysfunction and oxidative stress are central drivers of cardiometabolic diseases such as diabetes, where sustained reactive oxygen species burden accelerates EC senescence and barrier failure. These findings suggest its potential role in combating vascular aging and atherosclerosis; however, the underlying mechanisms remain partially understood.

In this study, we investigated whether TZ can prevent atherosclerosis in ApoE-/- mice fed a high-cholesterol diet and aimed to elucidate the mechanisms involved. Our results showed that TZ significantly reduced plaque size, EC senescence, vascular permeability, and reactive oxygen species (ROS) levels, effectively inhibiting atherosclerosis independently of α1-AR signaling.

In cultured primary human umbilical vein ECs (HUVECs), TZ inhibited EC senescence via the Pgk1/Hsp90 pathway. It enhanced the interaction between Hsp90 and the antioxidant enzyme peroxiredoxin 1 (Prdx1), leading to lower reactive oxygen species levels - a key driver of cellular senescence. These findings were confirmed in atherosclerotic ApoE-/- mice.

Furthermore, senescent ECs exhibited increased levels of vascular endothelial growth factor A (VEGFA) and decreased levels of angiostatin, contributing to higher vascular permeability and exacerbating atherosclerosis. TZ effectively reversed these changes.

Overall, our study demonstrates that TZ primarily alleviates EC senescence and atherosclerosis through the Pgk1/Hsp90/Prdx1 pathway, highlighting Pgk1 activation as a strategy that may also mitigate endothelial dysfunction and oxidative stress in broader cardiometabolic contexts (e.g., diabetes), suggesting that TZ is a promising senomorphic agent for treating vascular aging and that Pgk1-targeted interventions could have implications beyond atherosclerosis.

Link: https://doi.org/10.1186/s12933-025-02976-2

The aging of the extracellular matrix is not as well studied as is the case for cell biochemistry. There are likely many important changes that take place in the extracellular matrix over a lifetime that meaningfully affect cell function in aged tissues, but have yet to be discovered and understood. One example is outlined here, a matrix protein that declines with age but seems necessary to maintain the normal function of muscle stem cells. Declining muscle stem cell function is one of the important contributions to the characteristic loss of muscle mass and strength that occurs with age.

Skeletal muscle regeneration occurs through the finely timed activation of resident muscle stem cells (MuSC). Following injury, MuSC exit quiescence, undergo myogenic commitment, and regenerate the muscle. This process is coordinated by tissue microenvironment cues, however the underlying mechanisms regulating MuSC function are still poorly understood.

Here, we demonstrate that the extracellular matrix protein Tenascin-C (TnC) promotes MuSC self-renewal and function. Mice lacking TnC exhibit reduced number of MuSC, and defects in MuSC self-renewal, myogenic commitment, and repair. We show that fibro-adipogenic progenitors are the primary cellular source of TnC during regeneration, and that MuSC respond through the surface receptor Annexin A2. We further demonstrate that TnC declines during aging, leading to impaired MuSC function. Aged MuSC exposed to soluble TnC show a rescued ability to both migrate and self-renew in vitro.

Overall, our results highlight the pivotal role of TnC during muscle repair in healthy and aging muscle.

Link: https://doi.org/10.1038/s42003-025-09189-z

Even in this age of single cell sequencing, a great deal of the categorization and counting of cells is still accomplished via assessment of cell surface proteins. The ability to cheaply create and manufacture novel antibodies that selectively bind to specific proteins naturally led to technologies such as flow cytometry that can separate and count cells that express a specific surface protein, or high versus low levels of that surface protein. The large number of proteins with names that start with "CD" for cluster of differentiation are so named because researchers have spent a lot of time looking for ways to distinguish different populations of immune cells with very different behaviors.

Recognizing specific surface markers is also an important foundation for the development of cell killing technologies and immunotherapies. Thus the cancer research field is very interested in categorizing cells by their markers. Similarly, now that the research community recognizes that senescent cells accumulate with age and are harmful, an important contribution to age-relaed loss of function and disease, there is interest in distinct markers of senescence. Firstly, senescent cells are not uniform, and it may be useful to distinguish their types. Secondly, cell killing technologies that are highly selective for senescent cells are very much a desirable goal. Thirdly, the well established approaches to assess the burden of senescence in tissues are likely suboptimal in a number of ways.

The exploration of markers of senescence is a work in progress, with ongoing debate over the merits of one approach over another, particularly when it comes to the immune system. To come full circle, cellular senescence in the immune system appears important to immune system aging - but so are a range of other issues. The immune system is very complex, and far from fully mapped. There is a great deal of room for improvement to the present state of knowledge, and today's open access paper is an example of this sort of ongoing work on the topic of immune cell senescence and how to best identify this state.

Re-evaluating CD57 as a marker of T cell senescence: implications for immune ageing and differentiation

Ageing is accompanied by a decline in immune function, associated with susceptibility to infections and malignancies, and reduced vaccine efficacy. These immunological changes, affect multiple components of the immune system, particularly T lymphocytes, which exhibit altered subset distributions and accumulate senescent features.

CD57, a surface glycoprotein expressed on T cells, has emerged as a potential marker of terminal differentiation and senescence used for immunomonitoring in infection or cancer contexts. However, the use of CD57 as a marker of T cell senescence remains unclear. To investigate this, we analyzed CD57 expression on CD8+ and CD4+ T cells in healthy donors from two independent cohorts, considering cellular differentiation, age, cytomegalovirus status, and other senescence markers.

Our findings reinforce the association between CD57 expression, T cell differentiation, and cytomegalovirus seropositivity, but not with chronological age. Although CD57 is associated with altered proliferation and survival in all T cell differentiation subsets, it does not fully align with a senescent phenotype. Therefore, we propose that CD57 may be better appreciated as a marker of immunological age. Moreover, the interpretation of CD57 expression must account for cytomegalovirus serostatus to avoid misleading conclusions, especially in oncology and ageing research.